JPH0332558B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to stable aqueous solutions of alpha-tocopherol phosphates. α-Tocopherol improves peripheral blood circulation and is effective in treating numbness and coldness in the hands and feet, chilblains, and menopausal symptoms. In recent years, it has also been expected to be effective against cataracts. α-Tocopherol is an oily substance found in wheat germ, etc., and its acetate, nicotinate,
All calcium salts, such as succinate, are lipophilic and not water soluble. The present inventors focused on the phosphoric acid ester of α-tocopherol in order to obtain an aqueous solution of α-tocopherol. α-Tocopherol phosphate is hardly soluble in water in its free form, but its disodium salt is soluble in water. However, it is not only salted out from aqueous solution by salts such as sodium chloride, but also has a pH of approximately
10.5, making it unsuitable for use as injections or eye drops. Furthermore, in order to bring the pH close to physiological, acid is added to the aqueous solution to bring the pH to around 7, and if the solution is left at room temperature or thawed after freezing, the viscosity increases and the solution becomes cloudy, which is undesirable from a pharmaceutical standpoint. As a result of repeated research to overcome these shortcomings, the present inventors have completed the present invention. The present invention is characterized in that α-tocopherol phosphate is dissolved as a pharmaceutically acceptable water-soluble salt, its pH is 3 to 9, and a nonionic surfactant is added. It is a stable aqueous solution of α-tocopherol phosphate. As the pharmaceutically acceptable water-soluble salt of α-tocopherol phosphate, a water-soluble salt formed from α-tocopherol phosphate and a pharmaceutically harmless base is used. Metal salts, preferably sodium salts and potassium salts, may be mentioned. Other alkali metal salts, such as lithium salts, may be used if desired. The above water-soluble salts may be isolated in salt form and added to water to form an aqueous solution, but an aqueous solution of the salt obtained by reacting α-tocopherol phosphate and a base in water may be used as is. You may use it. The preferred concentration of α-tocopherol phosphate in the aqueous solution is 0.01 to 5 (W/V)%. The pH of the aqueous solution is selected in the range of 3 to 9, preferably 5 to 8. For this purpose, acids such as hydrochloric acid, acetic acid, sodium hydroxide,
Adjust the PH using an alkali such as sodium carbonate. When α-tocopherol phosphate is reacted with a base in water to obtain an aqueous solution of a water-soluble salt, for example, sodium hydroxide salt is used as the base to adjust the desired pH within the above range.
An aqueous solution of the sodium salt of α-tocopherol phosphate having the pH value is obtained. Also, α−
When the disodium salt of tocopherol phosphate ester is dissolved in water, an aqueous solution having a relatively high pH is obtained as described above, and an acid such as hydrochloric acid may be added to this to adjust the pH to a desired value. Various types of nonionic surfactants are currently available, but in the present invention, it is desirable to use those with HLB 11 to 20. Preferred types of nonionic surfactants include, for example, polyoxy lower alkylene ester types such as polyoxyethylene higher fatty acid esters, polyoxy lower alkylene ester types such as higher aliphatic alcohol polyoxyethylene ethers, and alkylphenol polyoxyethylene ethers. Ether types, polyhydric alcohols such as sorbit or sorbitan, or their dehydrates, in which some hydroxyl groups form polyoxyethylene ether and other hydroxyl groups form esters with higher fatty acids, and polyoxyethylene derivatives of castor oil. Examples include ether ester type. The nonionic surfactant is 15 (W/W)% or more based on α-tocopherol phosphate 200
(W/W)%, preferably 30 (W/W)% or more 100
(W/W)% is preferably used. If too little surfactant is used, the stabilizing effect tends to decrease. α-Tocopherol phosphate can be derived from α-tocopherol. The mode of its synthesis is shown below. [Synthesis of α-tocopherol phosphate ester] 6.12 g of phosphorus oxytrichloride (POCl ₃ ) was added to benzene.
Dissolve in 50ml, cool, and add DL-α-
A mixture of 8.6 g of tocopherol and 9.5 g of pyridine dissolved in 50 ml of benzene was added dropwise with stirring, and then the mixture was returned to room temperature and stirred for 3 hours. next,
1 ml of water was added to this under cooling, and the mixture was stirred for 30 minutes. After separating the precipitated pyridine hydrochloride, the benzene was distilled off, and the remaining oil was extracted with ethyl acetate.
After washing with hydrochloric acid and water and drying over dry sodium sulfate, ethyl acetate is distilled off. Residual oily substance 1~
Dissolve in 2% sodium hydroxide, filter through Celite if there are any insoluble materials, add sodium chloride to the solution to collect the white precipitate, wash this thoroughly with acetone, dehydrate, and after drying, Dissolve in water, filter, add hydrochloric acid to the solution, extract with ethyl acetate, wash with water, dry with sodium sulfate, and distill off the ethyl acetate to obtain about 9 g of a pale yellow oil (crystals when left standing). . This is recrystallized from petroleum ether or n-hexane. [Production of α-tocopherol phosphate disodium salt] 5 g of the above α-tocopherol phosphate ester
Suspend it in 1 part of water, add 10% sodium hydroxide solution, dissolve it, adjust the pH to 10.5, add about 40g of sodium chloride, and remove the white precipitate. , thoroughly washed with acetone and then ether, and dried. You will get about 4.5g. The effects of the present invention are remarkable. As an example, Tables 1, 2, and 3 show the changes in appearance when a nonionic surfactant is added to the aqueous solution of sodium α-tocopherol phosphate according to Test Formulation Examples 1 and 2 and thawed after 10 hours of freezing. Shown below. Test formulation example 1 Disodium α-tocopherol phosphate 0.3 (W/V)% Mannitol 5.0 〃 Nonionic surfactant 0.1 〃 Acetic acid (PH adjuster) Appropriate amount Sterile purified water Total amount 100 〃 PH7

【table】

[Table] Test formulation example 2 α-tocopherol phosphate disodium Each concentration (W/V) % Mannitol 5 〃 POE (20) Sorbitan monooleate
Each concentration 〃 Acetic acid (PH adjuster) Appropriate amount Sterile purified water Total amount 100 〃

【table】

[Table] POE is an abbreviation for polyoxyethylene, and the number in parentheses indicates the number of moles added. The degree of turbidity becomes mild in the order of appearance judgment, , +, and 1 indicates transparency. Table 1 shows various nonionic surfactants 0.1 (W/
The addition of V)% showed an effect on preventing cloudiness, and Table 2 shows that the addition of PH
This figure shows the relationship between the concentration of α-tocopherol phosphate disodium and the concentration of POE (20) sorbitan monostearate in 7. It is nonionic with respect to α-tocopherol phosphate disodium (weight). Surfactant is approximately 30 (W/
The effect was significant above W)%. Furthermore, Table 3 shows the relationship between changes due to pH and surfactants. In other words, at PH10, transparency can be maintained even without the addition of surfactants, but injections,
Eye drops and the like are not desirable in terms of irritation. Furthermore, when comparing pHs of 9, 8, and 7 at the same concentration of α-tocopherol phosphate, it was found that the lower the pH, the more surfactant was required. The present invention will be explained below with reference to Examples. Example 1 Injection α-tocopherol phosphate disodium
0.5g Glucose 5.0〃 POE (20) Sorbitan Monooleate 0.3〃 Acetic acid (PH adjuster) Appropriate amount of distilled water for injection Total volume 100ml (Adjust to PH7.0) Aseptically filter the above mixture and aseptically prepare a 2ml colorless ampoule. Fill 2 ml of the solution into a tube, melt it, and use it as an intramuscular injection. Example 2 Injection α-tocopherol phosphate disodium
2.0g Glucose 5.0〃 POE (60) Hydrogenated castor oil 1.0〃 Acetic acid (PH adjuster) Appropriate amount Distilled water for injection Total volume 100ml (Adjust to PH7.0) Aseptically filter the above mixture and aseptically make a 2ml color ampoule Fill 2 ml of the solution into a tube, melt it, and use it as an intramuscular injection. Example 3 Eye drops α-tocopherol phosphate 0.1g Mannitol 5.0〃 POE (20) Sorbitan monooleate 0.05〃 Sodium edetate 0.01〃 5% sodium hydroxide (PH adjuster) Appropriate amount Benzalkonium chloride 0.007〃 Sterilized and purified Total volume of water: 100ml (adjust to pH 7.2) Pass the above mixture aseptically, aseptically fill 10ml portions into eye drop bottles, and seal tightly to make eye drops. Example 4 Lotion α-tocopherol phosphate 0.5g POE (60) hydrogenated castor oil 0.5〃 Glycerin 4.0〃 Citric acid 0.1〃 Methyl paraoxybenzoate 0.1〃 Ethanol 15.0ml 5% potassium hydroxide (PH adjuster) Appropriate amount Sterilized purified water, total volume 100ml (adjust to PH6.0) Sterilize the above mixture, fill it into a 100ml lotion bottle, seal it, and use it as a lotion. Example 5 Drink α-tocopherol phosphate 0.1g L-ascorbic acid 0.5〃 Citric acid 0.2〃 Taurine 1.0〃 Inosit 0.5〃 Nicotinic acid amide 0.03〃 Honey 5.0〃 POE (40) monostearate 0.1〃 50% water Sodium oxide (PH adjuster) Appropriate amount of sterile purified water Total volume 100ml (Adjust to PH3.0) Aseptically filter the above mixture, aseptically fill it into a 100ml drink bottle, seal it tightly, and use it as a drink. Example 6 Syrup α-tocopherol phosphate disodium
3.0g POE (40) Monostearate 1.0〃 Sorbitol 70 (W/V) liquid 75ml Acetic acid (PH adjuster) Appropriate amount Methyl paraoxybenzoate 0.028g Pyropyl paraoxybenzoate 0.012g Sterile purified water Volume 100ml (adjusted to PH6.5) ) Pass the above mixture aseptically, aseptically fill it into a 50ml glass bottle, seal it tightly, and use it as a syrup.

Claims (1)

[Claims] 1. α-Tocopherol phosphate is dissolved as a pharmaceutically acceptable water-soluble salt, and its pH is 3.
9 to 9, and a stable aqueous solution of α-tocopherol phosphate, characterized in that it contains a nonionic surfactant. 2. The aqueous solution according to claim 1, wherein the pharmaceutically acceptable aqueous salt is an alkali metal salt. 3 HLB with 11 to 20 nonionic surfactants
An aqueous solution according to claim 1, which has the following. 4. The aqueous solution according to claim 1, wherein the amount of nonionic surfactant relative to α-tocopherol phosphate is 15% (W/W) or more. 5. The aqueous solution according to claim 1, to which at least one of sugars or alcohols is added as an isotonic agent. 6. The aqueous solution according to claim 1 obtained by dissolving an alkali metal salt of α-tocopherol phosphate in water, adjusting its pH to 3 to 9, and adding a nonionic surfactant. .